enzyme)-inhibitory protein] and cellular inhibitor of apoptosis protein 1 (c-IAP1) and decreased levels of FADD (Fas-associated via death domain), Fas ligand, and caspases. Death receptors are also sequestered within these cells.40 Indeed, death ligand expression by endothelial cells can induce apoptosis in invading inflammatory cells as a protective mechanism.41,42 Endothelial cells and vascular smooth muscle cells, however, can be primed to undergo death ligand-induced apoptosis by cytokines or stimuli that traffic death receptors to the cell surface, such as interferon-γ,43 nitric oxide,44 and p5345 or that downregulate protective genes such as inhibitors of apoptosis (IAPs).46 Atherosclerosis itself increases the sensitivity of both endothelial cells and vascular smooth muscle cells to undergo apoptosis. Both macrophages and cytotoxic T cells47,48,49 can induce apoptosis in these cells.44,50 In addition, plaque vascular smooth muscle cells show increased sensitivity to apoptosis compared with their normal counterparts.21 Increased sensitivity can occur via overexpression/activation of p53,51 with subsequent reduction in survival signaling such as that mediated by insulin-like growth factor 1 (IGF-1). For example, oxidative stress (e.g., as it occurs within an atherosclerotic plaque) can induce post-translational modification of p53 that renders it competent to repress IGF-1 receptor (IGFR) transcription.52 In addition, IGF-1 signaling can also be dampened by oversecretion of IGF-1 binding proteins from plaque vascular smooth muscle cells.53

2.2.4. Necrosis and autophagy in atherosclerosis

Little is known about the role of nonapoptotic forms of cell death in atherosclerosis. There is evidence that cultured macrophages, vascular smooth muscle cells, and endothelial cells can undergo necrosis and/or autophagic cell death in response to experimental stimuli.54,55,56,57 It remains unclear, however, whether these forms of cell death take place in intact atherosclerotic plaques and if so, contribute to the pathogenesis of atherosclerosis.

3. CELL DEATH IN THE MYOCARDIUM

Myocardial infarction and heart failure are the most common and lethal heart syndromes. Death of cardiac myocytes is a critical component in the pathogenesis of both, although the quantities and kinetics of cell death in each differ greatly.

The defining feature of myocardial infarction is the acute death of large numbers of cardiac myocytes during a relatively short interval (hours to <1 day). The

precipitant is ischemia, defined as decreased blood flow in one of the coronary arteries, the vessels that feed the heart muscle itself. Ischemia is precipitated by the rupture of an atherosclerotic plaque in the coronary artery (Figure 26-2). Typically, before rupture, atherosclerotic plaques cause only minor to moderate obstruction of the coronary artery. After rupture, the recruitment of platelets leads to rapid and sustained thrombotic occlusion. The consequences of myocardial infarction can be acute (arrhythmias, sudden death, structural damage to the heart) and long term (arrhythmias, sudden death, and heart failure).

Heart failure can most easily be thought of as a “weakening” of the heart muscle such that the strength of contraction is inadequate to propel blood to meet the metabolic needs of the body. There are many underlying causes of heart failure. These include hypertension, valvular heart disease, congenital heart disease, congenital cardiomyopathies, and toxins. Among the most common, however, is the occurrence of prior myocardial infarction(s) (Figure 26-2). Myocardial infarction elicits heart failure through two pathophysiologic mechanisms: (1) acute loss of functioning heart muscle from the infarction itself (infarct zone), and (2) long-term, pathological post-infarct remodeling in regions of the heart that were not involved in the myocardial infarction (noninfarcted myocardium). Remodeling of the noninfarcted myocardium is triggered by a complex array of mechanical, humoral, and neural pathways that sense the loss of functioning heart muscle in the infarct zone. Cardiac myocytes exhibit activation of a variety of stress pathways, leading initially to myocyte widening and thickening of heart chamber walls. At advanced stages, however, myocytes elongate, walls become thin, cardiac chambers dilate, and contractile function deteriorates. Cardiac myocyte death often ensues during this progression. These remodeling changes characterize not only the failing noninfarcted myocardium after myocardial infarction, but also the myocardium in advanced heart failure of any etiology.

In contrast to the robust, relatively short-lived burst of cell death during myocardial infarction, the magnitude of cardiac myocyte death in the failing heart is only modestly elevated (discussed in Section 3.2). However, cells can continue to die over the protracted course of heart failure, which may be months to several years in humans. This can result in significant cumulative loss of cells over the course of the disease. In the discussion that follows, we will consider the various death programs that operate during myocardial infarction and heart failure and the causal effects of cell death on cardiac function.